The future of pharmacogenetics in the treatment of heart failure

Heart failure is a common disease with high levels of morbidity and mortality. Current treatment comprises β-blockers, ACE inhibitors, aldosterone antagonists and diuretics. Variation in clinical response seen in patients begs the question of whether there is a pharmacogenetic component yet to be identified. To date, the genes most studied involve the β-1, β-2, α-2 adrenergic receptors and the renin-angiotensin-aldosterone pathway, mainly focusing on SNPs. However results have been inconsistent. Genome-wide association studies and next-generation sequencing are seen as alternative approaches to discovering genetic variations influencing drug response. Hopefully future research will lay the foundations for genotype-led drug management in these patients with the ultimate aim of improving their clinical outcome.</p

Tailoring therapy for heart failure: the pharmacogenomics of adrenergic receptor signaling.

Heart failure is one of the leading causes of mortality in Western countries, and β-blockers are a cornerstone of its treatment. However, the response to these drugs is variable among individuals, which might be explained, at least in part, by genetic differences. Pharmacogenomics is the study of genetic contributions to drug response variability in order to provide evidence for a tailored therapy in an individual patient. Several studies have investigated the pharmacogenomics of the adrenergic receptor system and its role in the context of the use of β-blockers in treating heart failure. In this review, we will focus on the most significant polymorphisms described in the literature involving adrenergic receptors and adrenergic receptor-related proteins, as well as genetic variations influencing β-blocker metabolism

Pharmacogenetics of asthma therapeutics

Asthma is recognised to arise from complex interactions between environmental exposure and disease-susceptibility genetic contributions.1 Pharmacological management of the condition aims to relieve symptoms, decrease airway hyperresponsiveness, and optimize the quality of life in patients. Inter-patient variability in the clinical responses to anti-asthma drugs is a recognized factor that may confound therapeutic outcome.peer-reviewe

A Physiologic approach to the pharmacogenomics of hypertension

Hypertension is a multifactorial condition with diverse physiological systems contributing to its pathogenesis. Individuals exhibit significant variation in their response to antihypertensive agents. Traditional markers, such as age, gender, diet, plasma renin level, and ethnicity, aid in drug selection. However, this review explores the contribution of genetics to facilitate antihypertensive agent selection and predict treatment efficacy. The findings, reproducibility, and limitations of published studies are examined, with emphasis placed on candidate genetic variants affecting drug metabolism, the renin-angiotensin system, adrenergic signalling, and renal sodium reabsorption. Single-nucleotide polymorphisms identified and replicated in unbiased genome-wide association studies of hypertension treatment are reviewed to illustrate the evolving understanding of the disease's complex and polygenic pathophysiology. Implementation efforts at academic centers seek to overcome barriers to the broad adoption of pharmacogenomics in the treatment of hypertension. The level of evidence required to support the implementation of pharmacogenomics in clinical practice is considered

Pharmacogenetics of inhaled long-acting beta2-agonists in asthma:a systematic review

Background: Long-acting beta2-agonists (LABA) are recommended in asthma therapy; however, not all asthma patients respond well to LABA. We performed a systematic review on genetic variants associated with LABA response in patients with asthma. Methods: Articles published until April 2017 were searched by two authors using PubMed and EMBASE. Pharmacogenetic studies in patients with asthma and LABA response as an outcome were included. Results: In total, 33 studies were included in this systematic review; eight focused on children (n = 6051). Nineteen studies were clinical trials, while 14 were observational studies. Studies used different outcomes to define LABA response, for example, lung function measurements (FEV1, PEF, MMEF, FVC), exacerbations, quality of life, and asthma symptoms. Most studies (n = 30) focused on the ADRB2 gene, encoding the beta2-adrenergic receptor. Thirty studies (n = 14 874) addressed ADRB2 rs1042713, 7 ADRB2 rs1042714 (n = 1629), and 3 ADRB2 rs1800888 (n = 1892). The association of ADRB2 rs1042713 and rs1800888 with LABA response heterogeneity was successfully replicated. Other variants were only studied in three studies but not replicated. One study focused on the ADCY9 gene. Five studies and a meta-analysis found an increased risk of exacerbations in pediatrics using LABA carrying one or two A alleles (OR 1.52 [1.17; 1.99]). These results were not confirmed in adults. Conclusions: ADRB2 rs1042713 variant is most consistently associated with response to LABA in children but not adults. To assess the clinical value of ADRB2 rs1042713 in children with asthma using LABA, a randomized clinical trial with well-defined outcomes is needed

BETA-ADRENORECEPTORS GENETIC POLYMORPHISM CONNECTION WITH BETA-BLOKER THERAPY EFFICACY IN PATIENTS WITH CARDIOVASCULAR DISORDERS

At present it is obvious that genetic peculiarities of patients are the major reason for individual differences in pharmacological responses to (β-adrenoblockers. Furthermore ADRB1 gene polymorphism is responsible for the efficiency of (β-adrenoblockers. Thus, a real prospect exists for an individualized approach to administration of (β-adrenoblockers and selection of dosage based on patient’s genotype, which must undoubtedly increase efficiency of the administered therapy. Reviewfocuses on gene polymorphism responsible for (β-adrenoblockers pharmacodynamics and on the clinical significance of the polymorphism detection to individualize drug therapy based on patient’s genotype

Farmaco-genetics: an individualized way of treating genetic disorders

Razlika u reakciji na lijek je vrlo česta kod pacijenata. U novije vrijeme, farmakogenetika se bavi mnoštvom reakcija na lijekove među pacijentima. Različita reakcija na lijek je uvjetovana raznim razlozima kao što su genetička konstitucija, okolišni čimbenici i doziranje lijeka. Otkrića farmakogenetike su društveno, medicinski, znanstveno i gospodarski bitni. U budućnosti će genetičko profiliranje populacije omogućiti zdravstvenoj skrbi predviđanje reakcije na lijekove i razvoj DNA testova. Ne možemo se uvijek osloniti na farmakogenetiku u reakciji na lijekove jer postoje i negenetički faktori koji mogu utjecati na reakciju i tako prouzročiti poteškoće pri dijagnozi i odabiru lijeka. Ipak, ušli smo u novu eru farmakogenetike, koja se čini jako obećavajućom u potpori donošenja terapeutske odluke, predviđanju pacijenata koji će najvjerojatnije dobro reagirati na određeni lijek ili kod kojih će lijek polučiti optimalne rezultate.The difference in drug response is very common among patients. Recently, phamacogenetics is dealing with variety of responses to medications for patients. The different response to drugs due to various reasons such as genetics constitutions, environmental factors and drug dosages. Findings from pharmacogenetics are socially, medically, scientifically and economically important. Genetic profiling of the population in the future will allow medical care predicting drug response or the development of DNA tests. We can not always rely on pharmacogentics base drug response because there are also non-genetic factors that can affect the response to drug, thus causing difficulty in diagnosis and choice of drug. Now, we have entered a new era with pharmacogenetics, which appear highly promising in enhancing the support to therapeutic decision- making, predicting patients who are most likely to respond best to a particular drug, or in whom the drug will yield optimal effects

Association of polymorphisms in the beta-2 adrenergic receptor gene with fracture risk and bone mineral density

Summary: Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms influence receptor function. We show that these polymorphisms are not associated with fracture risk or bone mineral density in the UCP, Rotterdam Study, and GEFOS cohorts. Introduction: Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms are known to influence receptor function in vitro and in vivo (rs1042713, rs1042714, and rs1800888). We examined the role of these polymorphisms in the B2AR gene on human bone metabolism. Methods: We performed nested case–control studies to determine the association of these polymorphisms with fracture risk in the Utrecht Cardiovascular Pharmacogenetics (UCP) cohort and in three cohorts of the Rotterdam Study. We also determined the association of these polymorphisms with bone mineral density (BMD) in the GEFOS Consortium. UCP contains drug-dispensing histories from community pharmacies linked to national registrations of hospital discharges in the Netherlands. The Rotterdam Study is a prospective cohort study investigating demographics and risk factors of chronic diseases. GEFOS is a large international collaboration studying the genetics of osteoporosis. Fractures were defined by ICD-9 codes 800–829 in the UCP cohort (158 cases and 2617 unmatched controls) and by regular X-ray examinations, general practitioner, and hospital records in the Rotterdam Study (2209 cases and 8559 unmatched controls). BMD was measured at the femoral neck and lumbar spine using dual-energy X-ray absorptiometry in GEFOS (N = 32,961). Results: Meta-analysis of the two nested case–control studies showed pooled odds ratios of 0.98 (0.91–1.05, p = 0.52), 1.04 (0.97–1.12, p = 0.28), and 1.16 (0.83–1.62, p = 0.38) for the associations betwee

Correction to the pathogenic alternative splicing, caused by the common GNB3 c.825C&gt;T allele, using a novel, antisense morpholino

The very common GNB3 c.825C&gt;T polymorphism (rs5443), is present in approximately half of all human chromosomes. Significantly the presence of the GNB3 825T allele has been strongly associated, with predisposition to essential hypertension. Paradoxically the presence of the GNB3 825T allele, in exon 10, introduces a pathogenic alternative RNA splice site into the middle of exon 9. To attempt to correct this pathogenic aberrant splicing, we therefore bioinformatically designed, using a Gene Tools® algorithm, a GNB3 specific, antisense morpholino. It was hoped that this morpholino would behave in vitro as either a potential “ splice blocker and/or exon skipper, to both bind and inhibit/reduce the aberrant splicing of the GNB3, 825T allele. On transfecting a human lymphoblast cell line homozygous for the 825T allele, with this antisense morpholino, we encouragingly observed both a significant reduction (from ~58% to ~5%) in the production of the aberrant smaller GNB3 transcript, and a subsequent increase in the normal GNB3 transcript (from ~42% to ~95%). Our results demonstrate the potential use of a GNB3 specific antisense morpholino, as a pharmacogenetic therapy for essential hypertension